Genetics Informatics Trial (GIFT) of Warfarin to Prevent DVT
NCT ID: NCT01006733
Last Updated: 2016-12-29
Study Results
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Basic Information
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COMPLETED
PHASE3
1598 participants
INTERVENTIONAL
2011-03-31
2016-11-30
Brief Summary
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Detailed Description
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Aim 1: To determine how pharmacogenetic-based warfarin therapy affects the safety and effectiveness of warfarin therapy. The intensity of anticoagulant therapy is measured by the International Normalized Ratio (INR). During initiation, the INR often falls outside the therapeutic range. INRs that are too low predispose patients to VTE while supratherapeutic INR values increase risk of bleeding.(4, 5) Previously, the FDA approved the label change of warfarin/Coumadin™ to recommend considering lower initial doses in patients known to have certain polymorphisms in genes affecting warfarin metabolism and sensitivity.(6) However, whether this strategy improves the safety and effectiveness of warfarin therapy in general is unknown. In particular, how this strategy affects subgroups with and without the genetic variants of interest is also unknown.
Hypothesis 1: Pharmacogenetic therapy decreases the composite risk of a non-fatal VTE, non-fatal major hemorrhage, death, or INR ≥ 4.0 in all patients, and/or in the subgroup of patients whose pharmacogenetic and clinical predicted therapeutic maintenance doses differ by \> 1.0 mg/day. Based on our meta-analysis of prior trials(7), we anticipate 80% power to simultaneously detect a 32% relative risk reduction in the composite outcome for
Aim 1 (as measured by a chi-square test). In the clinical arm, based on preliminary data, we anticipate that the rate of the composite outcome will be 15.7% in the clinical arm and 10.7% in the pharmacogenetic arm. We obtained these estimates because they average a rate of 13.2%, which is the rate of the composite outcome for Aim 1 observed from the initial 775 GIFT participants. The power was calculated using a two-sided alpha of 0.05 for a test of proportions, a drop-out rate of 2%, and a partitioned (two-sided) alpha with 0.044 allocated to the whole population and 0.01 to the high-risk subgroup. Because of correlation between these two subgroups, using these alphas preserves an overall type 1 error rate of 0.05.
Aim 2: To determine whether warfarin therapy with a target INR of 1.8 is non-inferior to therapy with a target INR of 2.5 at preventing VTE or death in orthopedic patients. One randomized trial (PREVENT) found that a target INR value of 1.5-2.0 prevented 64% of VTE recurrence.(8) Although that trial excluded orthopedic patients, such an approach has been endorsed by the American Academy of Orthopedic Surgeons (AAOS). On page 15 of the 2007 AAOS guidelines (9) they offer the following recommendation for VTE prophylaxis around the time of joint replacement: "Warfarin, with an INR goal of ≤ 2.0, starting either the night before or the night after surgery, for 2-6 weeks." However, the AAOS grade the overall evidence for VTE prophylaxis in this population as low (level III). The AAOS guidelines conflict with the prior American College of Chest Physician (ACCP) guidelines,(10) which recommend, as one of their (Grade 1A) options (page 338 S), using an "…adjusted-dose vitamin K antagonist (INR target, 2.5; range 2.0 to 3.0)." Because lower target INR values may reduce the risk of hemorrhage and simplify warfarin management(8) we propose to test the following:
Hypothesis 2: For prevention of non-fatal VTE or death, a target INR of 1.8 will be non-inferior to a higher target INR (2.5). Using a non-inferiority margin of 3% absolute risk reduction in non-fatal VTE or death and an estimated composite rate of 5.56% (based on preliminary GIFT data), we will have 83% power to detect the non-inferiority of a target INR of 1.8 in 1600 patients.
Conditions
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Keywords
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Study Design
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RANDOMIZED
FACTORIAL
PREVENTION
QUADRUPLE
Study Groups
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Target INR 1.8 and Pharmacogenetic
The target International Normalized Ratio (INR) is 1.8. Warfarin initiation is via Pharmacogenetic dosing.
Pharmacogenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Target INR 1.8
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
Target INR 2.5 and Pharmacogenetic
The target INR is 2.5. Warfarin initiation is via Pharmacogenetic dosing.
Pharmacogenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Target INR 1.8 and Clinical
The target INR is 1.8. Warfarin initiation is via clinical dosing.
Target INR 1.8
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
Target INR 2.5 and Clinical
The target INR is 2.5. Warfarin initiation is via clinical dosing.
No interventions assigned to this group
Interventions
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Pharmacogenetic
The pharmacogenetic arm estimates therapeutic warfarin dose using cytochrome P 450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P 450 4F2 (CYP4F2) genotype and clinical information. The clinical arm estimates warfarin dose from clinical information alone.
Target INR 1.8
We will randomize patients to a target International Normalized Ratio (INR) of 2.5 or 1.8.
Eligibility Criteria
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Inclusion Criteria
* must anticipate taking warfarin for at least 4 weeks for VTE prophylaxis after hip or knee arthroplasty
* must be able to give written, informed consent
* must have venous access
* must not be institutionalized, incarcerated at the time of enrollment (nursing home okay)
* must have life expectancy \> 6 months
* must have plans to have regular INR monitoring
* willing/able to follow-up in 3-7 weeks with a Doppler Ultrasound
Exclusion Criteria
* knowledge of CYP2C9, VKORC1, or CYP4F2 genotype
* knowledge of warfarin dose requirements from prior warfarin therapy
* absolute contraindication or allergy to warfarin therapy (e.g. pregnancy)
* receiving or planning to receive any anticoagulant besides warfarin (if low molecular weight heparin (LMWH) or subcutaneous heparin is deemed necessary by the clinician after enrollment, such patients will be allowed to remain in the study)
* unlikely to be compliant (e.g. due to history of non-compliance, or alcoholism)
* known thrombophilia, bleeding disorder, or history of serious bleed in the past 2 years (unless caused by trauma)
* personal history of venous thromboembolism
65 Years
ALL
Yes
Sponsors
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National Heart, Lung, and Blood Institute (NHLBI)
NIH
Hospital for Special Surgery, New York
OTHER
Intermountain Health Care, Inc.
OTHER
University of Utah
OTHER
Rush University Medical Center
OTHER
University of Texas Southwestern Medical Center
OTHER
Washington University School of Medicine
OTHER
Responsible Party
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Principal Investigators
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Brian F Gage, MD, MSc
Role: PRINCIPAL_INVESTIGATOR
Washington University School of Medicine
Locations
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Rush University Medical Center
Chicago, Illinois, United States
Washington University in St. Louis, School of Medicine
St Louis, Missouri, United States
Hospital for Special Surgery, Weill-Cornell
New York, New York, United States
University of Texas Southwestern
Dallas, Texas, United States
University of Utah
Salt Lake City, Utah, United States
Intermountain Medical Center
Salt Lake City, Utah, United States
Countries
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References
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Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther. 2010 May;87(5):572-8. doi: 10.1038/clpt.2010.13. Epub 2010 Apr 7.
Ferder NS, Eby CS, Deych E, Harris JK, Ridker PM, Milligan PE, Goldhaber SZ, King CR, Giri T, McLeod HL, Glynn RJ, Gage BF. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost. 2010 Jan;8(1):95-100. doi: 10.1111/j.1538-7836.2009.03677.x. Epub 2009 Oct 30.
King CR, Deych E, Milligan P, Eby C, Lenzini P, Grice G, Porche-Sorbet RM, Ridker PM, Gage BF. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost. 2010 Oct;104(4):750-4. doi: 10.1160/TH09-11-0763. Epub 2010 Aug 5.
Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol. 2011 Feb 1;57(5):612-8. doi: 10.1016/j.jacc.2010.08.643.
Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9. doi: 10.1038/clpt.2011.185. Epub 2011 Sep 7.
Horne BD, Lenzini PA, Wadelius M, Jorgensen AL, Kimmel SE, Ridker PM, Eriksson N, Anderson JL, Pirmohamed M, Limdi NA, Pendleton RC, McMillin GA, Burmester JK, Kurnik D, Stein CM, Caldwell MD, Eby CS, Rane A, Lindh JD, Shin JG, Kim HS, Angchaisuksiri P, Glynn RJ, Kronquist KE, Carlquist JF, Grice GR, Barrack RL, Li J, Gage BF. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost. 2012 Feb;107(2):232-40. doi: 10.1160/TH11-06-0388. Epub 2011 Dec 21.
Do EJ, Lenzini P, Eby CS, Bass AR, McMillin GA, Stevens SM, Woller SC, Pendleton RC, Anderson JL, Proctor P, Nunley RM, Davila-Roman V, Gage BF. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J. 2012 Oct;12(5):417-24. doi: 10.1038/tpj.2011.18. Epub 2011 May 24.
Kawai VK, Cunningham A, Vear SI, Van Driest SL, Oginni A, Xu H, Jiang M, Li C, Denny JC, Shaffer C, Bowton E, Gage BF, Ray WA, Roden DM, Stein CM. Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014 Dec;15(16):1973-83. doi: 10.2217/pgs.14.153.
Bass AR, Rodriguez T, Hyun G, Santiago FG, Kim JI, Woller SC, Gage BF. Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop. 2015 Oct;39(10):2011-6. doi: 10.1007/s00264-015-2853-0. Epub 2015 Jul 9.
Hyun G, Li J, Bass AR, Mohapatra A, Woller SC, Lin H, Eby C, McMillin GA, Gage BF. Use of signals and systems engineering to improve the safety of warfarin initiation. J Thromb Thrombolysis. 2016 Nov;42(4):529-33. doi: 10.1007/s11239-016-1402-z.
Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Anderson JL, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple B, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Low-Intensity vs Standard-Intensity Warfarin Prophylaxis on Venous Thromboembolism or Death Among Patients Undergoing Hip or Knee Arthroplasty: A Randomized Clinical Trial. JAMA. 2019 Sep 3;322(9):834-842. doi: 10.1001/jama.2019.12085.
Gage BF, Bass AR, Lin H, Woller SC, Stevens SM, Al-Hammadi N, Li J, Rodriguez T Jr, Miller JP, McMillin GA, Pendleton RC, Jaffer AK, King CR, Whipple BD, Porche-Sorbet R, Napoli L, Merritt K, Thompson AM, Hyun G, Anderson JL, Hollomon W, Barrack RL, Nunley RM, Moskowitz G, Davila-Roman V, Eby CS. Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty: The GIFT Randomized Clinical Trial. JAMA. 2017 Sep 26;318(12):1115-1124. doi: 10.1001/jama.2017.11469.
Related Links
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pharmacogenetic and clinical warfarin dosing algorithms for trial
Other Identifiers
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HL097036-01
Identifier Type: -
Identifier Source: org_study_id